Psychosis May Accelerate Brain Aging

Patients with psychosis experience accelerated aging of the brain's frontoparietal and cingulo-opercular networks, new imaging data show.

The study, which included more than 400 participants, also showed that the efficiency of the frontoparietal network was normal in those with early psychosis but was reduced in patients with chronic psychosis, indicating that such decline occurs after disease onset.

"There is growing evidence that normal biological aging is accelerated in psychotic disorders," principal investigator Julia M. Sheffield, PhD, Vanderbilt University Medical Center, Nashville, Tennessee, said in a statement.

"One aspect of healthy aging is declining cognitive function and less efficient communication within brain networks supporting cognitive abilities, including planning, problem solving, and memory," Sheffield added.

The findings were published online recently in Biological Psychiatry.

Lack of Research

Reduction in connectivity within the frontoparietal and cingulo-opercular networks occurs during normal aging, a process that contributes to cognitive impairment, the researchers note.

However, patients with psychotic disorders demonstrate evidence of accelerated aging across multiple biological systems, including shorter telomere length, an increase in inflammatory markers, and functional deterioration in the context of cognitive decline.

Resting-state functional connectivity — which can be used to estimate the degree of interconnectivity between brain regions — is another marker of brain aging. Abnormal resting-state functional connectivity has been widely reported in those with psychotic disorders.

To date, only one trial has examined aging rates of functional networks in patients with schizophrenia. That investigation concluded that persons with schizophrenia experience accelerated rates of decline in efficiency in the frontoparietal and cingulo-opercular networks, although the study had several limitations.

In the current study, investigators leveraged a large sample of patients with early to chronic stages of psychosis. They sought to determine whether the frontoparietal and cingulo-opercular networks exhibit evidence of accelerated aging in patients with psychotic disorders, confirm associations between network efficiency and cognition, and determine whether reduced network efficiency is observed in early-stage psychosis.

The study included an initial cohort of 506 individuals who had participated in one of three MRI studies. Of these individuals, 197 acted as healthy control participants, and 309 had schizophrenia spectrum disorder or bipolar disorder type I with psychotic features. After various exclusion criteria were applied, the final sample included 240 patients with psychosis and 178 healthy control persons.

Resting-state functional MRI and cognitive data were obtained for all participants. Global efficiency, a measure of functional integration, was calculated for the frontoparietal and cingulo-opercular networks, as well as for the subcortical network and the visual network.

"Global efficiency yields a single metric estimating the potential for information transfer within a network and reflects network integration," the investigators write. Efficiency metrics calculated at each threshold were averaged to produce a single estimate for each network.

Associations with age and cognition were also assessed and compared between groups.

Accelerated Aging Patterns

Consistent with past findings in accelerated aging, the study showed significantly stronger relationships between efficiency and age in patients with psychosis (r = −0.37) than in healthy control persons (r = −0.16) in the cingulo-opercular network as well as in the frontoparietal network (r = −0.31 vs −0.05).

Accelerated aging was not observed in either the subcortical or visual networks, suggesting specificity for cognitive networks that decline earliest in healthy aging.

The research also replicated earlier findings by confirming that the efficiency of both the cingulo-opercular and frontoparietal networks correlated with cognitive function across all participants (rs > .11; ps < .031).

What's more, patients with chronic psychosis (P = .004), but not those with early psychosis (P = .553), exhibited significantly lower frontoparietal network efficiency than did healthy control persons.

"The accelerated decline was specific to cognitive networks, providing evidence that accelerated aging is not due to a global reduction in efficient communication across the whole brain," Sheffield said.

Accelerated aging of frontoparietal and cingulo-opercular networks has important implications for cognitive functioning among individuals with psychosis, a population already affected by significant cognitive impairment, the investigators note. In fact, activation of both networks supports domain-general cognitive ability.

"Reduced efficiency of these networks has now been associated with poorer general cognition in four independent datasets, providing strong evidence that the functional topology of these networks supports cognitive ability," the researchers write.

Such cognitive decline may ultimately play a role in mortality, they add.

"Given the recently shown impact of accelerated aging on functional outcome, accelerated decline of information integration within higher-order cognitive networks implies an accelerated decline of functional outcome, which may in turn contribute to the increased mortality rates in schizophrenia recently reported," they write.

These findings suggest the potential for interventions that target cognition during early psychosis, the investigators write.

Protecting or increasing connectivity and cognition during early psychosis may ultimately improve functional outcome, and even mortality, following the diagnosis of a psychotic disorder, they add.

Potential Progression Disrupter?

Commenting for Medscape Medical News, John Krystal, MD, Yale University School of Medicine, New Haven, Connecticut, said the findings offer new insight into a well-researched issue.

"The premature 'aging' or degeneration of cortical networks has been increasingly documented in association with schizophrenia," said Krystal, who was not involved in the research.

"However, we have very little insight into the underlying mechanisms. Linking these imaging findings to mechanism is a critical step to understanding the progression of schizophrenia so that we may disrupt it," he added.

Sheffield agreed that declines in network efficiency that seem to begin after the onset of illness are particularly important — and open the door to disrupting the progression.

"With advances in cognitive remediation and the positive impact of exercise on connectivity of these networks, our findings provide hope that young adults with recent-onset psychosis will benefit from interventions bolstering connectivity within these networks, potentially slowing down or normalizing the rate of decline in efficiency and, therefore, cognitive function," she said.

The study was supported by the Charlotte and Donald Test Fund and by the National Institute of Mental Health. The study authors have disclosed no relevant financial relationships.

Biol Psychiatry. Published online January 3, 2019. Abstract

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